15-Deoxyspergualin, a synthetic analog of spergualin, has the chemical structure as follows: ##STR1##
15-Deoxyspergualin and a process for its preparation is described in U.S. Pat. No. 4,525,299 to Umezawa et al., while U.S. Pat. No. 4,851,446 to Umezawa, deceased, et al. describes an immunosuppressing method comprising the administration of 15-deoxyspergualin and related compounds. The '299 and '446 Umezawa patents are each incorporated herein by reference thereto.
15-Deoxyspergualin has been shown to have clinical activity as an immunosuppressant, especially in the treatment of organ transplant rejection in humans. Preclinical animal models have shown activity of DSG in the treatment of rheumatoid arthritis, diabetes, lupus and multiple sclerosis. Thus, deoxyspergualin may well have efficacy in humans in the treatment of these and other autoimmune diseases such as psoriasis. Deoxyspergualin is also useful to suppress human anti-mouse antibody (HAMA) response and may have activity in treating certain types of tumors.
Beneficially, deoxyspergualin has a superior side effect profile as compared to other immunosuppressive compounds including azathioprine, prednisone, OKT3 and cyclosporin A, immunosuppressants now commonly used in the treatment of organ transplant rejections.
Disadvantageously, deoxyspergualin has a very low oral bioavailability, ranging from 2 to 6% depending on the mammalian species. The reason for this limited oral activity is likely due to its high polarity and therefore its poor penetration in the gut. Because deoxyspergualin exhibits limited passive permeation of either the gut or the skin, its administration is presently limited to parenteral infusion, for example, by intravenous, intramuscular, subcutaneous and other parenteral injection methods. Due to pharmacokinetic constraints, intravenous infusion is preferred, and typically takes about three hours. Thus, deoxyspergualin is not generally suitable for self-administration by the patient, and is limited to in-patient treatment by trained health care professionals at a hospital, clinic, etc. Moreover, such mode of administration can be unpleasant and inconvenient for the patient, and due to the need for hospital or clinic administration, increases substantially the cost of medical care. This is particularly disadvantageous in the immunosuppressive treatment of organ transplant recipients, who require chronic, often daily administration of an immunosuppressant. Such patients are thus limited in their choice of immunosuppressive agents to agents that can be administered on an out-patient basis. Therefore, these patients must often elect an agent for oral administration that has less efficacy or which causes undesirable side effects. The ability to administer deoxyspergualin by a route that would allow chronic administration would give these patients a highly desirable alternative therapy.
Applicants have now been found that deoxyspergualin compounds may be administered iontophoretically and at a flux such that a therapeutic level of deoxyspergualin is achievable in the blood stream of the patient. Accordingly, chronic and convenient out-patient administration of deoxyspergualin is possible in accordance with the present invention without using the invasive procedures of the prior art.